Disease states such as cancer may present with sites of a body having pH ranges below that of a neutral physiological pH between 7.0 and 7.4. These sites may include, for example, tumors. Targeting these sites may pose difficulties with certain types of treatment. However, they may also provide possibilities of effective tumor treatment for pH-sensitive methods that are capable of delivery of drugs, genetic material, and other chemical entities to these low-pH targets. Such methods of targeting tumor sites in the body may involve carriers that undergo a conformational change and release a drug, genetic material, or other chemical entity as cargo upon encountering a pH change within the body such as the pH change surrounding a tumor.
Efforts have been made to utilize pH-sensitive drug/gene delivery vehicles, such as amphiphilic block peptides (U.S. Patent Application Publication No. US 2010/0286069 A1, Nov. 11, 2010), GALA peptides (Advanced Drug Delivery Reviews 56 (2004) 967-985), pH (low) insertion peptide (pHLIP) peptides (PNAS 107 (2010) 4081-4086), and pH sensitive polymers (Macromolecular Research, 20 (2012) 224-233). In general, a pH change may induce a configurational change of the delivery vehicle, which will be termed a pH-induced phase transition. These drug delivery/release strategies relying on pH-induced phase transition typically require a pH change several times larger than the one taught here, i.e., their required pH change is typically from neutral pH to pH 4-6. Low pH values of 4-6 are present in some intracellular compartments (such as lysosome and endosome) but not in a typical extracellular environment of tumor; therefore, the current technology (GALA, pHLIP, etc.) is ineffective or less effective for tumor targeting. In addition to the drawback of requiring a large pH change to trigger the phase transition, there are other problems associated with the current technology.
Nanoparticles made of amphiphilic block peptides (with at least one hydrophilic block and at least one hydrophobic block) are intact until they enter cells, where they unfold, i.e., they undergo a phase transition, inside endosomes/lysosomes which provide a sufficiently low pH environment. Therefore, drug uptake is predicated on cell ingestion of nanoparticles, typically involving endocytosis, which is a slow and inefficient process. Moreover, nanoparticles made of amphiphilic block peptides are large, typically ˜200 nm, thus easily lost to resticuloendothelial system during blood circulation.
GALA is a membrane-perturbing peptide, each forming a helix from a random coil upon a pH change, and together several helices self organize to form a tubule with an inner pore channel at low pH. In this configuration, GALA can penetrate cell membrane's bilayer and transport substance through the pore channel. However, since each helix must have a minimum length to span the thickness of the bilayer, and several helices are required to form a pore channel, GALA is a relatively large peptide (30 amino acids), which adds to the cost of synthesis.
pHLIP are peptides that become hydrophobic at low pH, thus with a tendency to adhere to the cell membrane. Since it is hydrophilic at a neutral pH and often lacking positive charge, it does not afford protection to enzyme-vulnerable amino-acid drugs, genes, DNA, RNA, siRNA and smRNA, which are easily attacked by serum enzyme proteins during blood circulation. In general, peptide-digesting serum enzymes thrive in the hydrophilic environment.
Lastly, pH sensitive polymers typically contain segments that are difficult to digest or immune to enzyme-mediated degradation, thus biosensitive or toxic.
Therefore, there is a need for non-toxic and easily synthesized highly pH sensitive delivery vehicles that can protect drugs, dissolve in an extracellular environment in tumor, and release drug.